Two-tier hydrogel degradation to boost endothelial cell morphogenesis

Cell-responsive degradation of biofunctional scaffold materials is required in many tissue engineering strategies and commonly achieved by the incorporation of protease-sensitive oligopeptide units. In extension of this approach, we combined protease-sensitive and -insensitive cleavage sites for the far-reaching control over degradation rates of starPEG-heparin hydrogel networks with orthogonally modulated elasticity, RGD presentation and VEGF delivery. Enzymatic cleavage was massively accelerated when the accessibility of the gels for proteases was increased through non-enzymatic cleavage of ester bonds. The impact of gel susceptibility to degradation was explored for the 3-dimensional ingrowth of human endothelial cells. Gels with accelerated degradation and VEGF release resulted in strongly enhanced endothelial cell invasion in vitro as well as blood vessel density in the chicken chorioallantoic membrane assay in vivo. Thus, combination of protease-sensitive and -insensitive cleavage sites can amplify the degradation of bioresponsive gel materials in ways that boost endothelial cell morphogenesis.     

Six-month course of mild cognitive impairment and affective symptoms in late-life depression

Mild cognitive impairment (MCI) is frequent in patients with late-life depression. Previous studies indicate that cognitive performance in these patients is not or only marginally improved when they recover from depression. However, recovery from cognitive impairments due to depression may have a longer time course than recovery from affective symptoms. In a group of 34 elderly depressed patients (mean age: 73.4 years) admitted to a gerontopsychiatric day-clinic, severity of depression and cognitive performance were assessed before the initiation of treatment and were reassessed 6 months later. At admission, 18 of 34 patients (53%) fulfilled the criteria for MCI, with a preponderance of impairments in short-term memory and visuospatial capabilities. At the 6-month follow-up, cognitive performance had not significantly improved for the entire group; 12 of 27 patients (44%) still were fulfilling the criteria for MCI. No relationships could be ascertained between cognitive impairment or functional level and severity or course of depression. Patients with diurnal variations of the depressive symptomatology were less likely to fully recover from depression.     

Quantitative proteomic analysis of single pancreatic islets

Technological developments make mass spectrometry (MS)-based proteomics a central pillar of biochemical research. MS has been very successful in cell culture systems, where sample amounts are not limiting. To extend its capabilities to extremely small, physiologically distinct cell types isolated from tissue, we developed a high sensitivity chromatographic system that measures nanogram protein mixtures for 8 h with very high resolution. This technology is based on splitting gradient effluents into a capture capillary and provides an inherent technical replicate. In a single analysis, this allowed us to characterize kidney glomeruli isolated by laser capture microdissection to a depth of more than 2,400 proteins. From pooled pancreatic islets of Langerhans, another type of “miniorgan,” we obtained an in-depth proteome of 6,873 proteins, many of them involved in diabetes. We quantitatively compared the proteome of single islets, containing 2,000–4,000 cells, treated with high or low glucose levels, and covered most of the characteristic functions of beta cells. Our ultrasensitive analysis recapitulated known hyperglycemic changes but we also find components up-regulated such as the mitochondrial stress regulator Park7. Direct proteomic analysis of functionally distinct cellular structures opens up perspectives in physiology and pathology.     

Barriers and attitudes towards cervical cancer screening in primary healthcare in Poland - doctors’ perspective

Background

Physician associates (PA) form part of the policy-driven response to increased primary care demand and a general practitioner (GP) recruitment and retention crisis. However, they are novel to the primary care workforce and have limitations, for example, they cannot prescribe. The novel 1 year Staffordshire PA Internship (SPAI) scheme, introduced in 2017, was established to support the integration of PAs into primary care. PA interns concurrently worked in primary and secondary care posts, with protected weekly primary care focussed education sessions. This evaluation established the acceptability of PA interns within primary care.

Methods

All ten PAs from the first two SPAI cohorts, the nine host practices (supervising GPs and practice managers) and host practice patients were invited to participate in the evaluation. A conceptual framework for implementing interventions in primary care informed data collection and analysis. Data were gathered at three time points over the internship from practices, through discussions with the supervising GP and/or practice manager, and from the PAs via discussion groups. To enrich discussion data, PA and practices were sent brief surveys requesting information on PA/practice characteristics and PA primary care roles. Patient acceptability data were collected by the host practices. Participation at every stage was optional.

Results

By evaluation end, eight PAs had completed the internship. Seven PAs and six practices provided data at every time point. Five practices provided patient acceptability data. Overall PA interns were acceptable to practices and patients, however ambiguity about the PA role and how best to communicate and operationalise PA roles was revealed. An expectation-preparedness gap resulted in PAs needing high levels of supervision early within the internship. SPAI facilitated closure of the expectation-preparedness gap and its funding arrangements made the high supervision requirements more acceptable to practices.

Conclusions

The test-of-concept SPAI successfully integrated new PAs into primary care. However, the identified challenges risk undermining PAs roles in primary care before they have attained their full potential. Nationally, workforce leaders should develop approaches to support new PAs into primary care, including commitments to longer-term, sustainable, cohesive and appropriately funded schemes, including structured and standardised education and supervision.

     

HOW STABLE IS STABLE? DEFINING AND MEASURING HOUSING STABILITY

Despite housing stability being a key concept in housing and homelessness policy, research, and service provision, it remains poorly defined and conceptualized, and to date there are no standard measures. We use in‐depth qualitative interviews with 51 young people transitioning away homelessness over the course of a year to examine the core dimensions of housing stability. Due to the potential for sudden change, we define housing stability as the extent to which an individual's customary access to housing of reasonable quality is secure. We define housing security among 8 main dimensions: housing type, recent housing history, current housing tenure, financial status, standing in the legal system, education and employment status, harmful substance use, and subjective assessments of housing satisfaction and stability. Based on these dimensions, we suggest a brief 13‐question scale that measures housing security.     

Nephrogenic systemic fibrosis with a spectrum of clinical and histopathological presentation: a disorder of aberrant dermal remodeling

Background: Nephrogenic fibrosing dermopathy (NFD) has emerged as a clinicopathologic entity since 1997 and recently renamed as nephrogenic systemic fibrosis (NSF). The etiology and pathogenesis remain uncertain. Characteristic clinical presentation is described as diffuse thickening and hardening of the skin occurring in patients with renal insufficiency. Typical histological features include proliferation of CD34 positive fibrocytes, increased thick collagen bundles and mucin deposition, without significant inflammatory infiltrate. Variations in clinical presentations have been reported, including papular and plaque‐like skin lesions, focal lesion only, as well as systemic involvement. Histological changes can be subtle and non‐specific, overlapping with other disease processes and harboring features including calcification and osteoclast‐like giant cells with osseous metaplasia. Methods: We reviewed patients with NSF that presented to our dermatology clinic by chart review, clinical examination and histological examination. Skin biopsy specimens were obtained from all cases. Histopathology evaluations were carried out by three dermatopathologists (AD, BS and GK) independently and the features were compared among all the cases. Special stains and immunohistochemistry study were also performed to highlight the histological features. Results: Seven cases of NSF presented with a spectrum of clinical manifestations, from classic diffuse hardening of the skin to localized linear plaques. On histological examination, proliferation of CD34‐positive fibrocytes ranged from sparse to dense, collagen bundles ranged from thin to thick, and the interstitial dermal mucin accumulation ranged from scant‐patchy to abundant. In addition, the lesion displayed various degrees of vascular proliferation, inflammatory infiltrates and intensities of CD68 and Factor XIIIa staining. Two cases showed extensive dermal calcification and ossification. Conclusion: NSF may present with a spectrum of clinical abnormalities, and exhibit overlapping histopathological features resembling cicatrix and other dermal reparative/regenerative processes. NSF may in fact to be a disorder of aberrant extracellular matrix remodeling in patients with renal insufficiency. Deng A, Bilu Martin D, Spillane A, Chwalek J, St. Surin‐Lord S, Brooks S, Petrali J, Sina B, Gaspari A, Kao G. Nephrogenic systemic fibrosis with a spectrum of clinical and histopathological presentation: a disorder of aberrant dermal remodeling.     

Prediction of treatment response to rivastigmine in Alzheimer's dementia

OBJECTIVES: To predict the treatment response to rivastigmine in patients with Alzheimer's dementia using neuropsychological and EEG data. METHODS: A neuropsychological examination and a quantitative EEG study were done in 20 patients with Alzheimer's dementia before initiating treatment with rivastigmine. After one week of treatment a second EEG examination was done. Therapeutic efficacy was determined six months after treatment initiation. Treatment response was defined as improvement in short term memory after six months of rivastigmine treatment. RESULTS: For the group of patients as a whole, there was a significant improvement in short term memory and orientation during rivastigmine treatment. The mini-mental state score improved from 20.2 to 21.7 (NS). In the EEG, theta power decreased significantly after one week of treatment. Treatment responders had a greater decrease in theta power after one week of treatment and a better short term memory at baseline than non-responders. Decrease in theta power during rivastigmine treatment and baseline short term memory were good predictors of treatment response. CONCLUSIONS: Generally available neuropsychological and EEG data may be useful for predicting response to rivastigmine in patients with Alzheimer's disease.     

Segregation of caffeine reward and aversion in the rat nucleus accumbens shell versus core

Caffeine, the most commonly consumed psychoactive drug in the world, is readily available in dietary sources, including soft drinks, chocolate, tea and coffee. However, little is known about the neural substrates that underlie caffeine's rewarding and aversive properties and what ultimately leads us to seek or avoid caffeine consumption. Using male Wistar rats in a place conditioning procedure, we show that systemic caffeine at a low intraperitoneal dose of 2 mg/kg (or 100 µM injected directly into the rostral, but not caudal, portion of the ventral tegmental area) produced conditioned place preferences. By contrast, high doses of systemic caffeine at 10 and 30 mg/kg produced conditioned place aversions. These aversions were not recapitulated by a caffeine analog restricted to the periphery. Both caffeine reward and aversion were blocked by systemic D1‐like receptor antagonism using SCH23390, while systemic D2‐like receptor antagonism with eticlopride had smaller effects on caffeine motivation. Most important, we demonstrated that pharmacological blockade of dopamine receptors using α‐flupenthixol injected into the nucleus accumbens shell, but not core, blocked caffeine‐conditioned place preferences. Conversely, α‐flupenthixol injected into the nucleus accumbens core, but not shell, blocked caffeine‐conditioned place aversions. Thus, our findings reveal two dopamine‐dependent and functionally dissociable mechanisms for processing caffeine motivation, which are segregated between nucleus accumbens subregions. These data provide novel evidence for the roles of the nucleus accumbens subregions in mediating approach and avoidance behaviours for caffeine.